Ubiquilins (Ubqlns)—a family of ubiquitin-binding proteins—are involved in several protein degradation pathways and have been implicated in various neurodegenerative diseases. Ubqln1 regulates autophagosome maturation during autophagy-mediated degradation. We now show that Ubqln4 mediates the interaction between Ubqln1 and the autophagy machinery by recruiting Ubqln1 to LC3. This targeting of Ubqln1 to autophagosomes requires the Ubqln4 UBL domain and the Ubqln1 UBA domain. This study identifies a new role for Ubqln4, expanding the role for Ubqlns in protein degradation.

/pdf/ubiquilin4-is-an-adaptor-protein-that-recruits-ubiquilin1-to-17e9wa49qr.pdf

Ubiquilin4 is an adaptor protein that recruits Ubiquilin1 to the autophagy machinery

RING domains of E3 ligases promote transfer of Ub (ubiquitin) from the E2~Ub conjugate to target proteins. In many cases interaction of the E2~Ub conjugate with the RING domain requires its prior dimerization. Using cross-linking experiments we show that E2 conjugated ubiquitin contacts the RING homodimer interface of the IAP (inhibitor of apoptosis) proteins, XIAP (X-linked IAP) and cIAP (cellular IAP) 2. Structural and biochemical analysis of the XIAP RING dimer shows that an aromatic residue at the dimer interface is required for E2~Ub binding and Ub transfer. Mutation of the aromatic residue abolishes Ub transfer, but not interaction with Ub. This indicates that nuleophilic attack on the thioester bond depends on precise contacts between Ub and the RING domain. RING dimerization is a critical activating step for the cIAP proteins; however, our analysis shows that the RING domain of XIAP forms a stable dimer and its E3 ligase activity does not require an activation step.

Regulation of ubiquitin transfer by XIAP, a dimeric RING E3 ligase.

XIAP, the X-linked inhibitor of apoptosis protein, regulates cell death signaling pathways through binding and inhibiting caspases. Mounting experimental research associated with XIAP has shown it to be a master regulator of cell death not only in apoptosis, but also in autophagy and necroptosis. As a vital decider on cell survival, XIAP is involved in the regulation of cancer initiation, promotion and progression. XIAP up-regulation occurs in many human diseases, resulting in a series of undesired effects such as raising the cellular tolerance to genetic lesions, inflammation and cytotoxicity. Hence, anti-tumor drugs targeting XIAP have become an important focus for cancer therapy research. RNA–XIAP interaction is a focus, which has enriched the general profile of XIAP regulation in human cancer. In this review, the basic functions of XIAP, its regulatory role in cancer, anti-XIAP drugs and recent findings about RNA–XIAP interactions are discussed.

https://www.mdpi.com/2218-273X/10/11/1493/pdf

XIAP's Profile in Human Cancer.

IAPs: Modular regulators of cell signalling

Subunit architecture of the Golgi Dsc E3 ligase required for sterol regulatory element-binding protein (SREBP) cleavage in fission yeast.

Background: Inhibitor of apoptosis proteins (IAPs) belong to a pivotal antiapoptotic protein family that plays a crucial role in tumorigenesis, cancer progression, chemoresistance and poor patient-survival. X-linked inhibitor of apoptosis protein (XIAP) is a prominent member of IAPs attracting intense research because it has been demonstrated to be a physiological inhibitor of caspases and apoptosis. Recently, an evolutionarily conserved ubiquitin-associated (UBA) domain was identified in XIAP and a number of RING domain-bearing IAPs. This has placed the IAPs in the group of ubiquitin binding proteins. Here, we explore the three-dimensional structure of the XIAP UBA domain (XIAP-UBA) and how it interacts with mono-ubiquitin and diubiquitin conjugates. Principal Findings: The solution structure of the XIAP-UBA domain was determined by NMR spectroscopy. XIAP-UBA adopts a typical UBA domain fold of three tightly packed alpha-helices but with an additional N-terminal 3(10) helix. The XIAP-UBA binds mono-ubiquitin as well as Lys48-linked and linear-linked diubiquitins at low-micromolar affinities. NMR analysis of the XIAP-UBA-ubiquitin interaction reveals that it involves the classical hydrophobic patches surrounding Ile44 of ubiquitin and the conserved MGF/LV motif surfaces on XIAP-UBA. Furthermore, dimerization of XIAP-UBA was observed. Mapping of the self-association surface of XIAP-UBA reveals that the dimerization interface is formed by residues in the N-terminal 3(10) helix, helix alpha 1 and helix alpha 2, separate from the ubiquitin-binding surface. Conclusion: Our results provide the first structural information of XIAP-UBA and map its interaction with mono-ubiquitin, Lys48-linked and linear-linked diubiquitins. The notion that XIAP-UBA uses different surfaces for ubiquitin-binding and self-association provides a plausible model to explain the reported selectivity of XIAP in binding polyubiquitin chains with different linkages.

/pdf/structural-analysis-of-the-uba-domain-of-x-linked-inhibitor-1maqx15zei.pdf

Structural analysis of the UBA domain of x-linked inhibitor of apoptosis protein reveals different surfaces for ubiquitin-binding and self-association

X-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) has been implicated as a novel tumor suppressor, which was proposed to exert pro-apoptotic effect by antagonizing the anticaspase activity of XIAP. Here, we delineated the domain architecture of XAF1 by applying limited proteolysis and peptide mass fingerprinting analysis. Our results indicated that XAF1 has a distinct domain organization, with a highly compact N-terminal domain (XAF1NTD) followed by a middle domain (XAF1MD), a 42-residue unstructured linker and a C-terminal domain (XAF1CTD). The search of XIAP binding region within XAF1 revealed that a modest affinity XIAPRING binding site (dissociation constant, Kd, ∼18 μM) is located at the C-terminal portion of XAF1. This C-terminal region, embracing XAF1CTD and a flexible tail at C-terminus (residue Thr251-Ser301), is functionally identified as XIAPRING-binding domain of XAF1 (XAF1RBD) in the present study. We have also mapped the interaction sites for XAF1RBD on XIAPRING by using NMR spectroscopy. By applying in vitro ubiquitination assay, we observed that XAF1RBD/XIAP interaction is essential for the ubiquitination of GST-XAF1RBD fusion protein. In addition, the C-terminal XAF1 fragment harboring XAF1RBD was found to be substantially ubiquitinated by XIAPRING. Base on these observations, we speculate a possible role of XAF1RBD in targeting XAF1 for XIAP-mediated ubiquitination.

Domain organization of XAF1 and the identification and characterization of XIAP(RING) -binding domain of XAF1.

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Structural analysis of the UBA domain of x-linked inhibitor of apoptosis protein reveals different surfaces for ubiquitin-binding and self-association

Domain organization of XAF1 and the identification and characterization of XIAP(RING) -binding domain of XAF1.